Characterizing Molecular Responses to Astrocyte-Specific Excitatory DREADD Activation and Calcium Extruder Expression in Relation to Alcohol Use Disorder

An estimated 15 million people in the United States suffer from Alcohol Use Disorder (AUD), and current pharmacological treatment is not very effective. A goal of AUD research is to understand neuroadaptations that occur in response to alcohol consumption, and to identify molecular targets for potential new treatments. Most AUD and other brain disease research has focused on neuronal mechanisms, but there is increasing interest in the role of glial cells in these disease states. Astrocyte-specific DREADD activation of Gq-GPCR signaling has been shown to increase alcohol consumption in rodents as well as change the sensitivity to specific alcohol-related behaviors. Investigating the impact of DREADD activation and alcohol exposure on neuronal and astrocytic function would provide insight into the mechanism behind astrocyte DREADD regulation of behavior. The mechanisms underlying the behavioral effects of astrocyte calcium manipulation are still unknown, and it is currently unclear how astrocyte calcium signaling in the PFC affects neuronal activity at baseline levels and in response to ethanol exposure. We provide early promising results of the cell and molecular responses to astrocyte-specific calcium manipulation to be followed up on. There was little effect on neuronal activity in the PFC by astrocyte-specific DREADD activation or the expression of an astrocyte-specific calcium extruder protein. However, we found that astrocyte calcium activation may interact with neuronal responses to alcohol exposure in the PFC. Finally, based on established pathways between the PFC and NAc brain regions, this research points to astrocyte-specific DREADD activation in the PFC affecting neuronal activity in the NAc.Neuroscienc

Admission for COPD Exacerbation Is Associated with the Clinical Diagnosis of Pulmonary Hypertension: Results from a Retrospective Longitudinal Study of a Veteran Population

<p>Patients with chronic obstructive pulmonary disease and pulmonary hypertension (PH–COPD) have an increased risk of hospitalizations and death compared to COPD alone. Identifying PH in COPD is challenging because performing right heart catheterization, the gold standard for PH diagnosis, is invasive and not routinely performed. Clinical characterization of COPD patients at risk who are progressing toward PH will aid therapeutic development at earlier stages of progressively fatal PH–COPD. We studied the records of 5,45,086 patients in a large Veterans Affairs healthcare network (2000–2012) with a primary discharge diagnosis of COPD based on encounters' ICD-9 codes and further stratified into those who received an additional ICD-9 code for a PH diagnosis. Patients with PH–COPD were assigned to one of the four subgroups: those with (a) no history of exacerbation or hospital admissions, (b) history of exacerbations but no hospital admissions, (c) hospital admissions unrelated to COPD and (d) history of COPD exacerbation-related hospital admissions. We also examined the COPD and COPD-PH cohorts for associated comorbidities such as cardiac disease and the presence of obstructive sleep apnea (OSA). A regression analysis revealed that patients with COPD exacerbation-related hospital admissions had 7 × higher risk of having a concomitant clinical diagnosis of PH compared to non-hospitalized patients. COPD-PH patients had higher rates of cardiac comorbidities (89% vs. 66%) and OSA (34% vs. 16%) compared to COPD alone. We conclude that COPD patients hospitalized for COPD exacerbations are at a higher risk for developing PH, and hospitalized COPD patients with cardiac comorbidities and/or OSA should be screened as at-risk population for developing PH.</p

Self-gated, dynamic contrast-enhanced magnetic resonance imaging with compressed-sensing reconstruction for evaluating endothelial permeability in the aortic root of atherosclerotic mice

High-risk atherosclerotic plaques are characterized by active inflammation and abundant leaky microvessels. We present a self-gated, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) acquisition with compressed sensing reconstruction and apply it to assess longitudinal changes in endothelial permeability in the aortic root of Apoe−/− atherosclerotic mice during natural disease progression. Twenty-four, 8-week-old, female Apoe−/− mice were divided into four groups (n = 6 each) and imaged with self-gated DCE-MRI at 4, 8, 12, and 16 weeks after high-fat diet initiation, and then euthanized for CD68 immunohistochemistry for macrophages. Eight additional mice were kept on a high-fat diet and imaged longitudinally at the same time points. Aortic-root pseudo-concentration curves were analyzed using a validated piecewise linear model. Contrast agent wash-in and washout slopes (b1 and b2) were measured as surrogates of aortic root endothelial permeability and compared with macrophage density by immunohistochemistry. b2, indicating contrast agent washout, was significantly higher in mice kept on an high-fat diet for longer periods of time (p = 0.03). Group comparison revealed significant differences between mice on a high-fat diet for 4 versus 16 weeks (p = 0.03). Macrophage density also significantly increased with diet duration (p = 0.009). Spearman correlation between b2 from DCE-MRI and macrophage density indicated a weak relationship between the two parameters (r = 0.28, p = 0.20). Validated piecewise linear modeling of the DCE-MRI data showed that the aortic root contrast agent washout rate is significantly different during disease progression. Further development of this technique from a single-slice to a 3D acquisition may enable better investigation of the relationship between in vivo imaging of endothelial permeability and atherosclerotic plaques' genetic, molecular, and cellular makeup in this important model of disease